Metabolism

Biologists at Whitehead Institute and MIT have discovered a vulnerability of brain cancer cells that could be exploited to develop more-effective drugs against brain tumors.

Scientists in the lab of Whitehead Institute Member David Sabatini have for the first time identified a protein that appears to be a nutrient sensor for the key growth-regulating mTORC1 metabolic pathway. 

Protein production or translation is tightly coupled to a highly conserved stress response—the heat shock response and its primary regulator, heat shock factor 1 (HSF1)—that cancer cells rely on for survival and proliferation, according to Whitehead Institute researchers. In mouse models of cancer, therapeutic inhibition of translation interrupts HSF1’s activity, dramatically slowing tumor growth and potentially rendering drug-resistant tumors responsive to other therapies.

A team of scientists from Whitehead Institute and the University of Texas Southwestern Medical Center has added markedly to the job description of prions as agents of change, identifying a prion capable of triggering a transition in yeast from its conventional single-celled form to a cooperative, multicellular structure. This change, which appears to improve yeast’s chances for survival in the face of hostile environmental conditions, is an epigenetic phenomenon—a heritable alteration brought about without any change to the organism’s underlying genome.

One enzyme, RagA, has been found to regulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway in cells according to glucose and amino acid availability. When this regulation breaks down in fasting newborn mice, the animals suffer a nutritional crisis and die.

By teasing apart rapamycin’s activity at the cellular level, researchers at Whitehead Institute and the University of Pennsylvania have determined that inhibiting only the protein cluster known as the mechanistic target of rapamycin complex 1 (mTORC1) prolongs life in mice without adversely affecting glucose tolerance or insulin sensitivity.

Using a new in vivo screening system, Whitehead Institute researchers have identified a protein in a key metabolic pathway that is essential in estrogen receptor (ER)-negative breast cancer.